Individualized dosing of oral propranolol for treatment of infantile hemangioma: a prospective study.

Introduction
infantile hemangioma is the most common benign tumor in infancy. Currently, oral propranolol is the treatment of choice for infantile hemangioma, but there is no consensus when it comes to its recommended dosage for this condition. Hence this study was conducted to find out the appropriate dosage of oral propranolol for treatment of infantile hemangioma.


Methods
A prospective study was conducted on 25 patients with infantile hemangioma, who were treated with gradually increasing dose of propranolol starting from a lower dose of 1mg/kg/day.


Results
17/22(76%) patients showed regression of the tumor at the dose of 1- 1.5 mg/kg/d. 5/22(24%) patients were unresponsive to the treatment with the lower dose and they did not respond even with the gradually escalated dose of 3-4 mg/kg/day.


Conclusion
Propranolol in a lower dose of 1-1.5 mg/kg/day is safe and efficacious in the treatment of infantile hemangioma and the lesions which do not show initial response to the lower dose are unlikely to respond to the higher dose of 3-4 mg/kg/day.

The prevalence of Infantile hemangioma in mature neonates is around 4.5% with a female (2.3-2.9 times higher) and white predominance [3]. The predominant locations are head and neck [4]. They arise in initial few weeks of life and then display a period of active growth followed by spontaneous involution. The proliferative phase spreads over three to six months. Most Infantile hemangiomas do not require therapy and regress spontaneously over months to years. However, about 10-15% of the cases result in complications such as obstruction, ulceration and disfigurement. It may also carry risk of bleeding. Treatment is required in such conditions [1]. Therapeutic effect of Propranolol over Infantile hemangioma was detected incidentally in the year 2008, when regression of facial hemangioma was noted in a child while being treated for hypertrophic cardiomyopathy by this molecule [5]. Since then, it is being used for infantile hemangioma and currently oral Propranolol is the treatment of choice for this condition [6].
However, there is lack of consensus over its dosage as cited in literature of different studies [7][8][9].
Propranolol has been used for cardiovascular indications in the dosage up to 4mg/kg/d, but for treatment of infantile hemangioma, a lower dose is required. For treatment of Infantile hemangioma, some studies favor a lower dose (1-1.5 mg/kg/dose) [7,8], while others favor a higher dose (3mg/kg/day) [9]. The precise mechanism of action of Propranolol in the treatment of infantile hemangioma is unclear. The possible mechanisms include vasoconstriction, inhibition of angiogenesis and induction of apoptosis [6]. Although Propranolol has been widely used for this indication, other Beta blockers like Nadolol [10][11][12][13] and Acebutolol [14] have also been shown to be effective for Infantile hemangioma in small non-controlled studies. Other agents with reported activity in treating Infantile hemangioma include corticosteroids, Interferon alpha and Vinca alkaloids [15]. Besides pharmacotherapy, other treatment modalities include Laser therapy and surgical resection.
Sometimes a combination of these modalities is required [16]. We conducted a prospective cross sectional study in 25 cases of infantile hemangioma to find out appropriate dosage of oral Propranolol for treatment of this condition.

Methods
Twenty seven patients of age 2 months and older, with vascular lesions suggestive of infantile hemangioma on clinical grounds, were selected. Approval from ethics committee of the institute was taken.
History of any hypoglycemic event with the child was enquired.
History of any heart block in the mother was also enquired in view of its potential association with complete heart block in the child. For this study, response was defined as 'subsided' when there was ≥ 90% reduction in size of tumor and 'partial' when reduction in tumor size was < 90%. Lei chang et al. used the similar parameter of measurement for labeling hemangioma as 'regression' and 'partial regression' after propranolol therapy [17]. In non-responders, the dose of propranolol was gradually increased at the rate of 0.5mg/kg/d every month till any response was observed or the maximum dose of 3-4mg/kg/dose was achieved. If no response was noted, one month after the maximum dose, propranolol was discontinued in them. In responder group, the criteria for tapering off propranolol was decided on the basis of subsidence of the tumor, decrease in tumor size and keeping the same size for 3 consecutive months and the child has received a minimum of 6 months of therapy. Follow up was done for 6 months after completion of therapy.

patients were started on oral Propranolol for treatment of their
Infantile hemangioma. There were 18 males and 7 females (Table   1). Head and neck region was predominantly involved (76%) with infantile hemangioma (Figure 1 [19]. After initial regression, the later improvement is much slower, sometimes with periods of stagnation. The treatment should be continued for at least 6 months because early cessation can cause a relapse [19].
Cessation of therapy before 1 year of age also may be associated with a relapse [20,21].
Page number not for citation purposes 4 Ultrasonography is a good tool for objective assessment of the change in tumor size [22]. Leaute-Labreze et al.conducted a controlled trial with 1mg/kg/d and 3 mg/kg/d of oral propranolol with approximately 100 patient in each group. They found complete or near complete resolution of the hemangioma after six months of oral propranolol in 50% of the patients in 1 mg/kg/d group as compared to 60% in 3 mg/kg/day group, but the side effects like hypotension was more common in 3mg/kg group (3% vs 1%).
Similarly Bronchospasm was more common in 3 mg/kg group compared to 1 mg/kg group (1% vs 0%) [23]. They observed that agitation as a side effect is more common in 1 mg/kg group (18%) as compared to 3 mg/kg(8%) group. This means that this side effect of propranolol is dose independent. We also observed irritability in 8% of children after starting propranolol therapy. This Inpatient management has been advocated for infants and children with -corrected gestational age of ≤ 8weeks, inadequate social support, comorbid conditions affecting the cardiovascular system, symptomatic airway hemangioma and history of hypoglycemia. As recurrence is more common if propranolol is stopped before 6 months of treatment or before 1 year of age of the child, it is logical to use lower dose for a longer period rather than higher dose for a shorter period.  Other modalities of therapy should be considered in them.

Competing interests
The authors declare no competing interests.

Authors' contributions
Arun Prasad, Amit Kumar Sinha and Bindey Kumar were involved in acquisition of data of the patient. Abhiranjan Prasad and Manju Kumari were involved in drafting the manuscript. All the authors have read and agreed to the final manuscript.

Acknowledgments
We are thankful to the patients and their parents and who contributed in this research.